Lesions of atherosclerosis become thickened and lead to clinical sequelae as a result of cell accumulation, connective tissue matrix formation, and an increase in intracellular and extracellular lipid. This program has identified many of these cellular changes and has defined specific changes in the extracellular matrix (ECM) that are associated with lesions and growth factor stimulation of vascular cells. An extension of these observations that many of these changes in the extracellular environment may promote lesion progression. The overall objective of this program project is to identify key regulatory elements transduced by the extracellular environment, both extracellular (Projects 1, 2, 4, 5, 6, 7) and intracellular the intimal accumulation of multiple cell types which are all being studied in our program: Lesions of atherosclerosis are due to the intimal accumulation of multiple cell types which are all being studied in our program: circulating cells (Project 4) that adhere and migrate across the endothelium; smooth muscle cells (Projects 1, 2, 6) that migrate from the media into the forming intima; and endothelial formation of neo- vessels (Projects 3, 4, 7) in advanced lesions that helps maintain the infiltration of inflammatory cells. Cell-cell (Project 4) and cell-matrix (Projects 1, 2, 3, 4, 6, 7) interactions, as well as intracellular and extracellular lipid accumulation (Project 5), are key regulators of the adhesion, migration, apoptosis, and proliferation that lead to the cell accumulation. To identify molecular mechanisms, endothelium, smooth muscle, and leukocytes will be probed in vitro (Projects 1, 2, 3, 4, 5, 6, 7), but their significance will also be tested in vivo (Projects 1, 2, 3, 4, 6, 7). By identifying key regulatory signals transduced by the extracellular environment, the proposed studies may suggest new approaches to the treatment of atherosclerosis and its complications.